Spironolactone in HFrEF: aldosterone blockade and survival benefit
Spironolactone blocks the receptor for the hormone aldosterone and improves survival in HFrEF, a failing heart whose left ventricle pumps out too small a share of its blood.
Remember
In HFrEF, aldosterone can escape suppression by an ACE inhibitor (a drug that blocks the enzyme making angiotensin II, the hormone that drives aldosterone release) and drift back towards baseline, and spironolactone is added to block its receptor and reduce mortality. It adds to the ACE inhibitor and does not replace it.
Aldosterone is a hormone made by the adrenal glands, and it makes the kidney hold on to sodium and water. It also promotes fibrosis, which is scarring of the heart muscle.
An ACE inhibitor lowers aldosterone at first. During long-term treatment, however, the suppression can be weak and unsustained, so aldosterone levels can drift back towards baseline. This is called aldosterone escape. Where aldosterone does drift back, the leftover hormone can keep stimulating its receptors in the kidney, heart and blood vessels. That contributes to salt and water retention and fibrosis, which can drive remodelling (the heart gradually changing shape and pumping less well).
Spironolactone is a mineralocorticoid receptor antagonist (MRA), a drug that blocks the receptor through which aldosterone acts. Aldosterone is still made, but spironolactone competes with it for its receptor and opposes its effects there. In HFrEF (heart failure with reduced ejection fraction: the left ventricle pumps out too small a share of its blood with each beat, an ejection fraction of 40% or less), an MRA is one of five drug classes with proven survival benefit, added when symptoms persist on an ACE inhibitor and a beta-blocker (a drug that slows the heart).
An MRA also gives a mild potassium-sparing diuresis (more sodium and water lost, potassium kept), but the survival benefit is not mainly due to that diuretic effect.
The main risk is hyperkalaemia (a high blood potassium), which is why potassium and kidney function are monitored.
Key facts
- Class
- spironolactone and eplerenone both block the aldosterone (mineralocorticoid) receptor.
- Mechanism
- it blocks the residual aldosterone signalling that can persist despite an ACE inhibitor (aldosterone escape).
- Added to
- the ACE inhibitor and the beta-blocker, and it does not replace them.
- Trials
- in RALES (severe heart failure, ejection fraction 35% or less, already on an ACE inhibitor), adding spironolactone cut the relative risk of death by 30%; in EMPHASIS-HF (patients with mild symptoms), eplerenone reduced deaths and hospital admissions.
- Main risk
- hyperkalaemia, so potassium and kidney function are checked within the first weeks of starting and after dose changes.
- Side effect
- spironolactone can also cause gynaecomastia (breast enlargement); eplerenone is more selective.
Exam traps
- Furosemide, a loop diuretic that makes the kidney pass more salt and water, clears congestion (fluid backing up in the lungs and tissues) but is not a drug that improves survival, so it is added for symptoms rather than to improve survival.
- Digoxin (a drug that weakly strengthens the heartbeat) eased symptoms and reduced hospital admissions in trials, but it did not reduce overall mortality, so it is not the drug to add for survival.
- Amiloride is also potassium-sparing, but it blocks the sodium channel itself rather than the aldosterone receptor, and in heart failure it is used to conserve potassium rather than to improve survival.
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